Summary of Work: Septic shock appears to result from excessive release of cytokines (e.g., tumor necrosis factor-alpha [TNF-alpha, and IL-2] and other pro-inflammatory substances [e.g., nitric oxide] from cells of the monocyte/macrophage lineage in response to infection or lipopolysaccharide (LPS) administration. The production of these cytokines, as well as their action, is mediated by signal transduction events, which induce protein tyrosine phosphorylation. Theoretically, inhibition of protein tyrosine phophorylation may be beneficial in sepsis. These compounds would block the potentially high cytokine production, which is dependent on tyrosine phosphorylation. These protein kinase inhibitors would block both activation and production of cytokinase by bacterial products and the effects of cytokines on target cells. Tyrphostins AG 126 and AG 556 are both protein kinase inhibitors that have been shown to improve outcome in small animal models durIng both LPS and live bacterial challenge. Further, both AG 126 and AG 556 have been shown to inhibit LPS-induced TNF production from dog peripheral blood mononuclear cells in vitro. Before human clinical trials, studies in a large animal model are needed to establish efficacy and safety of these compounds. In collaboration with Dr. Novogrodsky and his colleagues, we evaluated AG 126 and AG 556 in our canine peritonitis model. In a controlled trial in 100 animals over 6 months, AG 556, but not AG 126, significantly improved survival and prevented multi-organ failure during canine septic shock. This therapeutic agent is proceeding to human clinical trials.